N-substttuted dffiybronormorphine



N SUBSTITUTED DIHYDRONORMORPHINE COMPGUNDS Robert L. Clark, Woodhridge, N. 3., assignor to Merck & Co., Inc., Rahway, N. 3., a corporation of New Jersey No Drawing. Application November 22, 1952, Serial No. 322,143

9 Claims. (Cl. 260-285) This invention is concerned generally with novel derivatives of morphine and with processes for preparing these morphine derivatives. More particularly, it relates to novel N-substituted dihydronormorphine compounds having attached to the nitrogen atom the terminal carbon of a straight aliphatic chain consisting of three carbon atoms, to lower alkanoyl esters of these N-substituted dihydronormorphine compounds, to acid salts thereof, and to novel processes for preparing these compounds starting with dihydronormorphine or with the corresponding N- substituted normorphine compound. These N-substituted dihydronormorphine compounds, their esters, and salts thereof, are active as morphine antagonists.

The N-substituted dihydronormorphine compounds, their esters, and acid salts thereof, subject of the present invention, may be chemically represented by the following structural formulae:

N-HA

wherein R is hydrogen or a lower alkanoyl radical, Y is an aliphatic radical containing a straight chain consisting of three carbon atoms a terminal carbon of which is attached to the nitrogen atom, and HA is an acid.

The chemical relationship of these N-dihydronormorphine compounds, and their esters, to morphine is clear from a comparison of the foregoing formulae with the formula for morphine which is as follows:

N-CH:

2,741,612 Patented Apr. 10, 1956 This antagonistic action possessed. by the subject compounds is particularly surprisingin view of the fact that other N-alkyldihydronormorphine compounds such as N- methyldihydronormorphine (i. e. dihydromorphine), N-n-butyldihydronormorphine, N-amyldihydronormorphine, N-hexyldihydrononnorphine as well as the 3-methyl ether derivatives of the subject compounds exhibit no appreciable morphine antagonistic activity.

The N-substituted dihydronormorphine compounds having attached to the nitrogen atom the terminal carbon of a straight aliphatic chain consisting of three carbon atoms, the lower alkanoyl esters of these N-substituted dihydronormorphine compounds, and acid salts thereof, can be prepared by reactions which may be chemically represented as follows:

Compound 1 Compound 2 Compound 3 Acyletln agent 0 R 0 R Compound 4 Compound 5 wherein R is a lower alkanoyl radical, Y is an aliphatic radical containing a straight chain consisting of three carbon atoms a terminal carbon of which is attached to the nitrogen atom, X is a halo radical and HA is an acid.

The reactions indicated hereinabove are carried out as follows; Dihydronormorphine (Compound 1) is reacted with an aliphatic halide of the formula Y wherein X and Y have the significance defined hereinabove, thereby forming the corresponding N-substituted dihydronormorphine compound (Compound 2); the latter compound is reacted with an acid to produce the corresponding salt of said N-substituted dihydronorrnorphine compound (Compound 3); alternatively, the N-substituted dihydrononnorphine compound is reacted with a lower alkanoic anhydride thereby producing the corresponding 3,6-dialkanoyl N-substituted dihydronorrnorphine compound wherein the N-substituent is an aliphatic radical containing a straight chain consisting of three carbon atoms a terminal carbon of which is attached to the nitrogen atom (Compound 4), which is converted by reaction with an acid to the corre-. sponding acid salt of the 3,6-dialkanoyl N-substituted dihydronorrnorphine compound (Compound 5).

The aliphatic halides which react with dihydronormorphine to form my novel N-substituted dihydronormorphine compounds contain a straight aliphatic chain consisting of three carbon atoms the terminal carbon of which is attached to the halogen atom; in one preferred embodiment of my invention, a methyl grouping is connected to the middle carbon atom of this straight aliphatic chain. I prefer to employ as the aliphatic halide an n-propyl halide .such as n-propyl chloride, n-propyl bromide, n-propyl iodide, an isobutyl halide such as isobutyl chloride, isobutyl and the like.

6, bromide, isobutyl iodide, I an allyl halide such as allyl chloride, allyl bromide, allyl iodide, a methallyl halide such as methallyl chloride, methallylbromide, methallyl iodide,

and dihydronormorphine. is ordinarily conducted byzheate ingithe reactants together in: contact with-anacid-binding agent in aliquid' medium which is substantially inertunder' the reacti'on conditions, and which isI-a solveutfo-r the reactants; I prefer to utilize; aswthe liquid'medium; a lower-aliphatic alcohol suchzas-methanol, ethanoL-propanol and the like. The. liquid mediumemployedshouid be'substantially-frce of water; As the acid-binding: agent I ordinarily utilize'an alkali metaltcarbouate; such'as.

sodium carbonate: potassium carbonate; arr: aikali Imetal blcarbonate': such as sodium bicarbonate; potassium? hi carbonate,; an alkaline earth metalazcarbonate, such? escalrequired tocomplete the reactionbetween the-dihydronormorphine and the aliphatic halide.

In accordance with the foregoing procedure, there is obtained the corresponding. N-substituted dihydronormorphine compound having attached to the nitrogen atom the terminal carbon of a straight aliphatic chain consisting of three carbon atoms which may have a methyl grouping attached to the-middle carbon atom of said chain, as, for example, 1 -n-propyldihydronormorphine, N isobutyldihydronormorphine, N ally ldihydronormorphine, and N -rnethallyldihydronormorphiue=. The N- substituted dihydronormorphine compound is conveniently recovered by evaporating the organic solvent from the reaction mixture, preferablyunder reducedpressure, and extracting the residual material with a hot' chlorinated solvent such as chloroform. The chlorinated solvent extract is filtered thereby removing any tut-reacted dihydronormorphine since the latter compound isinsoluble in chlorinated solvents. The filtered solution: is evaporated to dryness to give the N-substituted dihydronormorphine compound in crude. form; this, crude material, can be rendered crystalline by trituration with ether or petroleum ether and the resulting material purified by recrystallization from. lower aliphatic alcohols such as methanol and etha 1101.

Alternatively, the N-substituted dihydronormorphine. compounds having attached to the. nitrogen atomate'rminal. carbon, of a straight aliphatic chain consisting of three carbon atoms may be prepared by hydrogenation of the corresponding N-substituted. norniorphine compounds. This procedure is ordinarily used, however, only for the preparation of N-alkyldihydronormorphinev compounds such as N-n-propyldihydronormorphine and N-isobutyldihydronormorphine since hydrogenation. of N-alkenylnormorphine compounds, such as N-allylnormorphine or N- methallylnormorphine, results in the formation of the corresponding N-alkyldihydronormorphine compound- The N-substituted normorphinecompounds utilized as starting materials intthisalternate procedure,-namely the N alkylnormorphine compounds, and theN-alkenylnora morphine compounds, can be prepared by reacting normorphine with the appropriate aliphatic halide; inwth'e presence of an acid-binding agent utilizing substantially the same procedure as, that described. hereinaboveinfcon-i' nection with the reaction.betweemdihydronormorphine and aliphatic halides- The-hydrogenation ofitheresulting N-substituted normorphine compounds suchas' N-n propylnormorphine," N isobntylnormofphine; N-allylnofimorphine, N-methallylnormorphine; and 'the'lilce, is'can The reaction between. the aliphatic-halide or in a lower alkanoic acid such as acetic acid, or aqueous solutions thereof, and bringing the resulting solution into intimate contact with hydrogen in the presence of a hydrogenation catalyst such as platinum, palladium, or halides thereof. In a preferred embodiment of my procedure,

the N-substituted norrnorphine compound is dissolved in an aqueous solution of acetic acid and the resulting-solution is intimately contacted with hydrogen at a pressure ried out by dissolving the" N -substituted' normorphine compound'in a lower aliphatic alcohol such as methanol somewhat below 190 pounds per'square inch, at a temperature of about 30 C.,' and in the presence of apalladiu-m catalyst. The N alkyldihydronormorphine compound thus produced can be recovered by filtering the hydrogenation mixture, makingthe filtered solutionalkaline with a base such as ammonium hydroxide, whereby the N- alkyldihydronormorphinecrystallizes therefrom and can be recovered by filtration.

The N-substituted dihydronormorphine compound having attached: to nitrogen atom a terminal carbonxofa straight-aliphatic chain consisting ofthree c rbon atoms is then reacted with a lower aliranoicanh tcdride .suclrasacetic anhydride,-propionic anhydriddzand the like, there by" esterifying thezhydroxylradicals in and 3- 311d.6"

positionsrof the :molecule to form the: corresponding 3,6- dialkanoiyl N-substituted dihydronormorphinecompoundhavingattachedto the nitrogen: atom'the terminal carbon:

of a1 straight aliphatic chainconsisting of threecarbon at0l1lSWhlCh' may have a methyl grouping attached to:

the middle carbon atom of said chain, as, for example, 3,6- diacetyl- N --(n propyl) dihydronormorph-ine, 3,6 dipropionyl N (n-propyl)-dihydronormorphine; 3,6-dibutyri- N (n-prepyll-dihydronormorphinc; 3,6 diacetyl N isobutyldihydronorntorphine, 3,6 dipropi'onyr! N-is'obutyldihydronormorphine; 3,6 dibutyryhN-isobutyldihydronormorphine, 3,6-diacetyl-N-allyldihydronormorphine; 3,6 dipropionyl N- allyldihydronormorphine; 3,6 dihutyryl N-allyldihydronormorphine; 3,6-diacetyl-N-methallyldihydronormorphine, 3,6-dipropionyl-N-methallyldihy- 'dronormorphine; 3,6 dibutyryl N-methallyldihydronormorphine, and the like.

The reactionibetween the alkanoic acid 'anhydride and the N-substituted dihydronormoiphine compound is ordinarily conducted by heating a mixture of the reactants to a temperature of about 100 C. for a period. of about two to three hours. The reaction mixture is then'evaporatcd under reduced pressure, and the residual material is purifled by recrystallization froma lower alkanol such as ethanol to give the 3,6-dialkanoyl N-snbstituted 'dihydronormorphine compound in substantially pureforrn.

The conversion of l l-substituted riih i1'onornior phine compounds; or-their lot 2r aii'tanoyl esters, the 3,6- dialkanoyhN substitutedddiydronormorphinecompounds, to'the-correspondingacid' saitsis ordirw conducted by reacting the i -suhstituteddihydronormorphin'esom pound or the 3,6-dialkanoyl-l*-substituted dihydronormorphine compound, under substantially anhydrous conditions, with an acid as for example, hydrogen chloride, hydrogen bromide, sulfuric acid, acetic acid, tartaric acid, citric acid, and the like. T 's salt-forming reaction is conveniently carried out dissolving the N-substituted dihydronormorphine compound, or the 3,6-d1alkauoyl-N- hot substituted dihydronormorpniue compound, in a lower alkanol, such as ethanol, methanol. ii the like, and adding to the solution a slig alcoholic solution of the appropriate acid. Upon di the resulting alcoholic medium with an alcohoi-rn nonsoivent for the product, such as diethyt ethm,

crystallizes fromthemixture (depending on whether N-substituted dihydronormorphine, its ester, is used.

drobromide, N-isobutyldihydronormorphine sulfate, N-npropyldihydronormorphine acetate, N-n-propyldihydronormorphine tartrate, N-isobutyldihydronormorphine acetate, N-isobutyldihydronormorphine tartrate, N-allyldihydronormorphine hydrochloride, N-allyldihydronormorphine hydrobromide, N-allyldihydronormorphine sulfate, N-allyldihydronormorphine tartrate, N-allyldihydronormorphine acetate, N-methallyldihydronormorphine hydrochloride, N-methallyldihydronormorphine hydrobromide, N-rnethallyldihydronormorphine sulfate, N-methallyldihydronormorphine tartrate, N-methallyldihydronormorphine acetate, 3,6-diacetyl-N-(n-propyD-dihydronormorphine hydrochloride, 3,6-diacetyi-N-(n-propyl)- dihydronormorphine hydrobromide, 3,6-diacetyl-N-(npropyl)-dihydronormorphine sulfate, 3,6-diacetyl-N-(npropyl)-dihydronormorphine acetate, 3,6-diacetyl-N-(npropyl)dihydronormorphine tartrate, 3,6-dipropionyl-N- (n-propyl)-dihydronormorphine hydrochloride, 3,6-dipropionyl-N-(n-propyl)-dihydronormorphine hydro'orornide, 3,6 dipropionyl-N-(n-propyl)-dihydronormorphine sulfate, 3,6 dipropionyl-N- (n-propyl)-dihydronormorphine acetate, 3,6-dibutyryl-N-(n-propyl)-dihydronormorphine hydrochloride, 3,6 dibutyryl-N-(n-propyl)-dihydronormorphine hydrobromide, 3,6-dibutyryl-N-(n-propyl)-dihydronormorphine sulfate, 3,6-dibutyryl-N-(n-propyl)- 'dihydronorrnorphine tartrate, 3,6-diacetyl-N-isobutyldihydronormorphine hydrochloride, 3,6-diacetyl-N-isobutyldihydronormorphine hydrobromide, 3,6-diacetyl-N-isobutyldihydronormorphine sulfate, 3,6-diacetyl-N-isobutyldihydronormorphine acetate, 3,6-diacetylN-isobutyldi hydronormorphine tartrate, 3,6-dipropionyl-N-isobutyldihydronormorphine hydrochloride, 3,6-dipropionyl-N- isobutyldihydronormorphine hydrobromide, 3,6-dipropionyl-N-isobutyldihydronormorphine sulfate, 3,6-dipropionyl-N-isobutyldihydronormorphine acetate, 3,6-dibutyryl N isobutyldihydronormorphine hydrochloride, 3,6 dibutyryl-N-isobutyldihydronormorphine hydrobromide, 3,6-dibutyryl-N-isobutyldihydronormorphine sulfate, 3,6-dibutyryl-1 -isobutyldihydronormorphine tartrate, 3,6-diacetyl-N-allyldihydronormorphine hydrochloride, 3,6-diacetyl-N-allyldihydronormorphine hydrobromide, 3,6-diacetyl-N-allyldihydronormorphine sulfate, 3,6-diacetyl-N-allyldihydronorrnorphine acetate, 3,6-diacetyl-N-allyldihydronorrnorphine tartrate, 3,6-dipropionyl-N-allyldd1ydronormorphine hydrochloride, 3,6-dipropionyl-N-allyldihydronorrnorphine hydrobromide, 3,6- dipropionyl-N-allyldihydronormorphine sulfate, 3,6-dipropionyl-N-allyldihydronormorphine tartrate, 3,6-dibutyryl-N-allyldihydronormorphine hydrochloride, 3,6-dibutyryl-N-allyldihydronormorphine hydrobromide, 3,6- dibutyryl-N-allyldihydronormorphine sulfate, 3,6-dibutyryl-N-allyldihydronormorphine acetate, 3,6-diacetyl-N- methallyldihydronormorphine hydrochloride, 3,6-diacetyl- N-methallyldihydronormoiphine hydrobromide, 3,6-diacetyl-N-methallyldihydronormorphine sulfate, 3,6-diacetyl-N-methallyldihydronormorphine acetate, 3,6-diacetyl-N-rnethallyldihydronormorphine tartrate, 3,6-dipropionyl- I-methallyldihydronormorphine hydrochloride, 3,6 dipropionyl-I-rnethallyldihydronormorphine hydrobromide, 3,6-dipropionyl-N-methallyldil1ydronormorphine sulfate, 3,6-dipropionyl-N-methallyldihydronormorphine acetate, 3,6-dibutyryl N methallyldihydronormorphine hydrochloride, 3,6-dibutyryl-N-methallyldihydronormorphine hydrobromide, 3,6-dibutyryl-N-methallyldihydronormorphine sulfate, 3,6-dibutyryl-N-methallyldihydronormorphine tartrate, and the like. The salt thus formed is recovered from the alcoholic slurry by filtration of centrifugation.

The following examples illustrate methods of carrying out the present invention, but it is to be understood that these examples are given for purposes of illustration and not of limitation.

Example 1 A mixture of 4 g. of dihydronormorphine, 1.28 ml. of allyl bromide, 1.79 g. of sodium bicarbonate and 50 ml.

of absolute ethanol was heated under reflux with stirring for a period of about seventeen hours. At the end of this period the solvent was evaporated in vacuo. The residual material was extracted twice with hot chloroform, the chloroform extracts were filtered to remove the insoluble inorganic material, and the clear chloroform extract was evaporated to dryness. The residual gummy material was dissolved in methanol and the solution was passed through a small column of alumina. The column was washed with methanol until the eluate no longer contained any solids. The methanolic solution of the free base was evaporated to dryness and the residual gummy material was dissolved in ethanolic hydrogen bromide; the solution was acidic. The crystalline material which separated was recovered by filtration and recrystallized from ethanol to give substantially pure N-allyldihydronormorphine hydrobromide, M. P. 263265 C.; [a] =ll3 (C, 0.5 in absolute ethanol). Analysis.- Calcd for C19Hz3NO3-HBr: C, 57.88; H, 6.13; N, 3.55. Found: C, 58.08; H, 6.25; N, 3.41.

Example 2 An aqueous solution of N-allyldihydronormorphine hydrobromide was made slightly alkaline by the addition of aqueous ammonium hydroxide solution and the resulting solution was extracted with ether. The ethereal extract was washed with water and evaporated to give an amorphous solid which crystallized upon standing. This material was recrystallized from ethyl acetate to give substantially pure N-allyldihydronormorphine, M. P. 179- 180 C. [a] =170 (C, 1 in ethanol).

Example 3 Seven hundred milligrams of N-allyldihydronormorphine were dissolved in 10 ml. of acetic anhydride, and the resulting solution was heated at a temperature of about C. for a period of approximately two and onehalf hours. The reaction mixture was evaporated nearly to dryness under reduced pressure to give crude 3,6-diacetyl-N-allyldihydronormorphine which is obtained as an amorphous residue. This residual material was dissolved in a warm solution containing 600 mg. of tartaric acid dissolved in absolute ethanol. The resulting solution was cooled, and the crystalline material which separated was recovered and recrystallized from ethanol to-give, in substantially pure form, the hemihydrate of the tartaric acid addition salt of N-allyldihydronormorphine diacetate; M. P. 107l13 C.; [a] =76 (C, 0.78 in absolute ethanol). Analysis.Calcd for C23I I2'INO5 CqHsOs 951- C, 58.37; H, 6.17. Found: C, 58.55; H, 6.35.

Example 4 A solution of 15.5 g. of N-allylnormoiphine hydrowas allowed to stand at room temperature for a period of about one hour, and the crystalline material which separated was recovered by filtration and recrystallized from ethyl acetate to give substantially pure N-n-propyldihydronormorphine; M. P. 23 l232 C., [a] =-15U; (C, 0.4 in absolute ethanol). Analysis.-Calcd for C, 72.35; H, 7.99; N, 4.44. Found: C, 72.46; H, 7.87; N, 4.24.

The N-ally1normorphine hydrochloride utilized as starting material in the foregoing procedure can be prepared as follows: 35 g. of normorphine and 7.95 g. of allyl eymiiera' bromide is dissolved-in 356*cc. of" chloroform t and the: solution is'heated in-a -sealed tube atatemperature of 110 Q'ffora period ofth'ree andone-halfihoursr The reaction material is filtered, and'theresidual solidrnaterial extracted with chloroform. The chloroform extract is evaporated to'dryness fn'vacuo, and the residual mate= rialistrituratedwith75 cc. of ether. 'I'h'e resulting mix ture' is cooled. to approximately'w' C.' and maintainedat that temperature fora 'periodof about twohours; The

precipitated 'material'is recovered from the resulting slurryby filtration, andis extracted for fifteen hours With anhydrous ether utilizing aSoxhlet extractor. The ether extract is evaporated in the absence of 'air to incipient.

slight excess of alcoholic hydrochloric acid is added to the solution whereupon a crystalline material separates rapidly from the resulting mixture. This crystalline materialis recovered by filtration, washed withcold alcohol and dried in vacuo to give substantially pure Nailylnormorphine hydrochloride.

Example -5 N-n-propyldihydronormorphine, prepared as described in Example 4 hereinabove, was dissolved in ethanolic hydrogen chloride, whereupon an'oily product. precipitated. Upon stirring the resulting mixture, the oily material crystallized, and this crystalline' material was recovered by filtration and recrystallized. fronrabsolute ethanol to givesubstantially'pure N-n-propyldihydronorrnorphine hydrochloride; M. P. l47149 C.; loc] =ll3 .5 (C, 1.5. inabsolute ethanol); analysis ofa sample dried at 78 C. and 1 mm. pressure: Calcd for N-n-propyldihydronorrnorphine hydrochloride monohydrate,

C19H25NO3 HC1-H20' C, 61.69; H, 7.63; found: C, 61.93;. H, 7.47.

' Exampled' A solution containing 325- mg. of N-methallylnormorr phinein 20 ml. of a 50% aqueous solution of acetic acid was reacted with hydrogen, ata pressure of about 40' rial in the foregoing procedure, can be prepared as-follows: A-mixture of 6.0 g. of normorphine; 2.68 g. of sodium bicarbonate, 2.3 ml.- of methallyl chloride; and

100 ml of absolute ethanolis heated under'reilux with stirrhzgforaperiod of-seventyfour hours.- At theend of period; the reaction,- mixtureis:filteredtherehy removing-insolublematerial. Therfiltered solution is; evap-' orated to. dryness under reduced pressure-and theresidual materialis, extracted twice withhot chloroform. The

chloroform extract is-evaporated to dryness. and-the residual material is triturated-with ether; The tan solid materialz'which"precipitates from the ethereal mixtur c is' dissolved in a 1- :1 mixture of acetonezmethanol; activated charcoal is added to the solution, and the resulting-min ture is filtered-r The filtered solution is-evaporated'to' small volume, and the-"white needles whi'ch; crystallize" from the ethereal solution are recovered by filtration and" dried to give substantially pure -N-methallylnorrnorphin'e; M. 216 c;

Example 7 N-isobutyldihydronormorphine prepared" as described in Example 6 hereinabove-,=was dissolved in ethanolic-hydrogen chloride;- whereupon an oily product precipitated.

Uponstirring the resulting mixture, the" oily material.

crystallized, and this crystalline material was recovered-by filtration and recrystallized from absolute ether to givesubstantially pure N-isobutyldiliyd-ronormorphine hydrochloride.

Various changes and modifications may be-r-nade incarryihg' out the present invention without departing-fromthespirit and'scopethereof. Insofar as thesechanges and modifications are within'the-purview of the annexed, claims; they: are to he considered as part of my invention.

' I claim:

1. A-compound-selected from thegroup'which consists of N- substituted dihydronormorphine compounds having attached to the nitrogen atom a radical selected from'the group consisting of N-n-propyl, N isobutyl', N-all'yl and N-methailyl"radicals, lower allianoyl esters of said N-substituted dihydronorrnorphine compounds, and acid ad I dition saltsth'ereof.

N-n-propyldihydronormorphine. N-n-propyldihydronormorphine hydrochloride. N-allyldihydronormorphine. N-allyldihydr'onormorphine sulfate. 3,6diacetyl-N-allyldihydronormorphine acetate. The process-whichcomprises reacting an N-substituted normorphinecornpound, having attached to the nitrogen-atom a' radical selected from thegroup consisting of N-n-propyl, N-isobutyl, N-allyl and N-methallylradicals, with hydrogen under pressure in the presence of a noble metal hydrogenation catalyst thereby forming the corresponding N-substituted dihydronorrnorphine compound.

8. The process which comprises reacting together, in a medium comprising aqueous acetic acid and in the presence of palladium chloride catalyst, N-allylnormorphine and hydrogen, thereby forming N-n-propyldihydronormorphine;

9. The process which comprises reacting together; in a medium comprising aqueous acetic acid and in the presence of palladium chloride catalyst, N-methall'ylnormorphine and hydrogen, thereby forming N-isobutyldihy dronormorphine.

References (Zited in the file of this patent- UNITED STATES PATENTS Germany Jan. 7, 193G OTHER REFERENCES McCaWley etal;: JACS, vol; 63, p. 314 (1941). Braun: Ber. 49, 977 89 (1916). 

1. A COMPOUND SELECTED FROM THE GROUP WHICH CONSISTS OF N-SUBSTITUTED DIHYDRONORMORPHINE COMPOUNDS HAVING ATTACHED TO THE NITROGEN ATOM A RADICAL SELECTED FROM THE GROUP CONSISTING OF N-N-PROPYL, N-ISOBUTYL, N-ALLYL AND N-METHALLYL RADICALS, LOWER ALKANOYL ESTERS OF SAID N-SUBSTITUTED DIHYDRONORMORPHINE COMPOUNDS, AND ACID ADDITION SALTS THEREOF. 